Interactions between hydrophobic drugs and endogenous gastrointestinal substances have the potential to manipulate drug concentration in the human gastrointestinal system, and thus likely play an important role in determining the rate of absorption for hydrophobic drugs. The effects of phospholipids, bile salts and digestive proteins on the solution behaviour of clofazimine in biorelevant media was demonstrated here using dissolution experiments and solid state analytical techniques. Clofazimine is a hydrophobic, anti-mycobacterial agent with virtually no detectable water solubility in its free base form. Salt forms of the drug offer improved aqueous solubility but are unstable in solutions at low pH (pH 1.6) or high pH (pH 6.5). At low pH and high chloride ion concentrations, CFZ in solution experiences a high driving force to crystallize from solution as a hydrochloride salt, which is insoluble, while at high pH CFZ does not dissolve to any extent. In this study, it is demonstrated that amphipathic compounds present in the gastric and intestinal systems can overcome the instability experienced by CFZ at these pH values. This is done by encapsulation of the hydrophobic drug in mixed bile salt phospholipid micelles in both the gastric and intestinal fluid, and by the drug actively binding with the digestive enzyme pepsin in the gastric system. Pepsin binds and solubilises the drug at even relatively low concentration (0.1 mg/mL). When pepsin concentration is increased in the gastric media, a corresponding increase in the solution stability of CFZ is observed.